Role of CagA in Helicobacter pylori Infection and Pathology

  • Takeshi Azuma


Gastric cancer is the second leading cause of cancer-related deaths worldwide (Parkin et al. 2001). Various epidemiologic studies identified a role for Helicobacter pylori in gastric carcinoma in humans (The Eurogast Study Group 1991; Kikuchi et al. 1995; Parsonnet et al. 1991). In 1994, the World Health Organization International Agency for Research on Cancer classified H. pylori as a group I carcinogen in humans (IARC 1994). CagA protein, encoded by the cagA gene, is one of the most studied virulence factors of H. pylori, and is a highly immunogenic protein. The cagA gene is one of many genes located within the pathogenicity island (PAI) known as the cag PAI. The presence of cagA is considered a marker for the presence of cag PAI (Covacci et al. 1993). The cagPAI is a 40-kb locus in the chromosomal glutamate racemase gene. Its G + C content (35%) differs from the G + C content of the remainder of the genome (39%), suggesting that it was acquired from another organism...


Gastric Cancer Pylorus Infection Focal Adhesion Kinase Tyrosine Phosphorylation Atrophic Gastritis 
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  1. Ahmad, S., Banville, D., Zhao, Z., et al. 1993. A widely expressed human protein-tyrosine phos-phatase containing src homology 2 domains. Proc Natl Acad Sci USA 90:2197–2201.CrossRefPubMedGoogle Scholar
  2. Amieva, M.R., Vogelmann, R., Covacci, A., et al. 2003. Disruption of the epithelial apical-junc-tional complex by Helicobacter pylori CagA. Science 300:1430–1434.CrossRefPubMedGoogle Scholar
  3. Asahi, M., Azuma, T., Ito, S., et al. 2000. Helicobacter pylori CagA protein can be tyrosine phos-phorylated in gastric epithelial cells. J Exp Med 191:593–602.CrossRefPubMedGoogle Scholar
  4. Azuma, T., Yamakawa, A., Yamazaki, S., et al. 2002. Correlation between variation of the 3'region of the cagA gene in Helicobacter pylori and disease outcome in Japan. J Infect Dis 186:1621–1630.CrossRefPubMedGoogle Scholar
  5. Azuma, T., Yamazaki, S., Yamakawa, A., et al. 2004. Variation in the SHP-2 binding site of Helicobacter pylori CagA protein is associated with gastric atrophy and cancer. J Infect Dis 189:820–827.CrossRefPubMedGoogle Scholar
  6. Backert, S., Moese, S., Selbach, M., et al. 2001. Phosphorylation of tyrosine 972 of the Helicobacter pylori CagA protein is essential for induction of a scattering phenotype in gastric epithelial cells. Mol Microbiol 42:631–644.CrossRefPubMedGoogle Scholar
  7. Bagnoli, F., Buti, L., Tompkins, L., et al. 2005. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci USA 102:16339–16344.CrossRefPubMedGoogle Scholar
  8. Blaser, M.J., Perez-Perez, G.I., Kleanthous, H., et al. 1995. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 55:2111–2115.PubMedGoogle Scholar
  9. Censini, S., Lange, C., Xiang, Z., et al. 1996. Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA 93:14648–14653.CrossRefPubMedGoogle Scholar
  10. Churin, Y., Al-Ghoul, L., Kepp, O., et al. 2003. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol 161:249–255.CrossRefPubMedGoogle Scholar
  11. Correa, P. 1988. A human model of gastric carcinogenesis. Cancer Res 48:3554–3560.PubMedGoogle Scholar
  12. Covacci, A., Censini, S., Bugnoli, M., et al. 1993. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci USA 90:5791–5795.CrossRefPubMedGoogle Scholar
  13. Covacci, A., Telford, J.L., Del Giudice, G., et al. 1999. Helicobacter pylori virulence and genetic geography. Science 284:1328–1333.CrossRefPubMedGoogle Scholar
  14. De Souza, D., Fabri, L.J., Nash, A., et al. 2002. SH2 domains from suppressor of cytokine signal-ing-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 41:9229–9236.CrossRefPubMedGoogle Scholar
  15. The Eurogast Study Group. 1993. An association between Helicobacter pylori infection and gastric cancer. Lancet 341:1359–1362.CrossRefGoogle Scholar
  16. Feng, G.S., Hui, C.C., Pawson, T. 1993. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 259:1607–1611.CrossRefPubMedGoogle Scholar
  17. Freeman, R.M., Jr., Plutzky, J., Neel, B.G. 1992. Identification of a human src homology 2-con-taining protein-tyrosine-phosphatase: a putative homolog of Drosophila corkscrew. Proc Natl Acad Sci USA 89:11239–11243.CrossRefPubMedGoogle Scholar
  18. Higashi, H., Tsutsumi, R., Fujita, A., et al. 2002a. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc Natl Acad Sci USA 99:14428–14433.CrossRefGoogle Scholar
  19. Higashi, H., Tsutsumi, R., Muto, S., et al. 2002b. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295:683–686.CrossRefGoogle Scholar
  20. Huang, J.Q., Zheng, G.F., Sumanac, K., et al. 2003. Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 125:1636–1644.CrossRefPubMedGoogle Scholar
  21. IARC. 1994. Schistosomes, liver flukes and Helicobacter pylori. Monographs on the evaluation of carcinogenic risks to humans. IARC Sci Publ 61:1–241.Google Scholar
  22. Ito, Y., Azuma, T., Ito, S., et al. 1997. Analysis and typing of the vacA gene from cagA-positive strains of Helicobacter pylori isolated in Japan. J Clin Microbiol 35:1710–1714.PubMedGoogle Scholar
  23. Ito, S., Azuma, T., Murakita, H., et al. 1996. Profile of Helicobacter pylori cytotoxin derived from two areas of Japan with different prevalence of atrophic gastritis. Gut 39:800–806.CrossRefPubMedGoogle Scholar
  24. Jackson, C.B., Judd, L.M., Menheniott, T.R., et al. 2007. Augmented gp130-mediated cytokine signalling accompanies human gastric cancer progression. J Pathol 213:140–151.CrossRefPubMedGoogle Scholar
  25. Kikuchi, S., Wada, O., Nakajima, T., et al. 1995. Serum anti-Helicobacter pylori antibody and gastric carcinoma among young adults. Research group on prevention of gastric carcinoma among young adults. Cancer 75:2789–2793.CrossRefPubMedGoogle Scholar
  26. Kodama, A., Matozaki, T., Fukuhara, A., et al. 2000. Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering. Mol Biol Cell 11:2565–2575.PubMedGoogle Scholar
  27. Mimuro, H., Suzuki, T., Tanaka, J., et al. 2002. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol Cell 10:745–755.CrossRefPubMedGoogle Scholar
  28. Murata-Kamiya, N., Kurashima, Y., Teishikata, Y., et al. 2007. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdif-ferentiation in gastric epithelial cells. Oncogene 26:4617–4626.CrossRefGoogle Scholar
  29. Neel, B.G., Gu, H., Pao, L. 2003. The “Shp”ing news: SH2 domain-containing tyrosine phos-phatases in cell signaling. Trends Biochem Sci 28:284–293.CrossRefPubMedGoogle Scholar
  30. Odenbreit, S., Puls, J., Sedlmaier, B., et al. 2000. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287:1497–1500.CrossRefPubMedGoogle Scholar
  31. Parkin, D.M., Bray, F.I., Devesa, S.S. 2001. Cancer burden in the year 2000. The global picture. Eur J Cancer 37:S4–S66.CrossRefPubMedGoogle Scholar
  32. Parsonnet, J., Friedman, G.D., Vandersteen, D.P., et al. 1991. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325:11127–11131.CrossRefGoogle Scholar
  33. Roovers, K., Assoian, R.K. 2000. Integrating the MAP kinase signal into the G1 phase cell cycle machinery. Bioessays 22:818–826.CrossRefPubMedGoogle Scholar
  34. Saadat, I., Higashi, H., Obuse, C., et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447:330–333.Google Scholar
  35. Satomi, S., Yamakawa, A., Matsunaga, S., et al. 2006. Relationship between the diversity of the cagA gene of Helicobacter pylori and gastric cancer in Okinawa, Japan. J Gastroenterol 41:668–673.CrossRefPubMedGoogle Scholar
  36. Segal, E.D., Cha, J., Lo, J., et al. 1999. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci USA 96:14559–14564.CrossRefPubMedGoogle Scholar
  37. Segal, E.D., Falkow, S., Tompkins, L.S. 1996. Helicobacter pylori attachment to gastric cells induces cytoskeletal rearrangements and tyrosine phosphorylation of host cell protein. Proc Natl Acad Sci USA 93:1259–1264.CrossRefPubMedGoogle Scholar
  38. Selbach, M., Moese, S., Hauck, C.R., et al. 2002. Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem 277:6775–6778.CrossRefPubMedGoogle Scholar
  39. Stein, M., Bagnoli, F., Halenbeck, R., et al. 2002. c-Src/Lyn kinase activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 43:971–980.CrossRefPubMedGoogle Scholar
  40. Stein, M., Rappuoli, R., Covacci, A. 2000. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci USA 97:1263–1268.CrossRefPubMedGoogle Scholar
  41. Suzuki, M., Mimuro, H., Suzuki, T., et al. 2005. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med 202:1235–1247.CrossRefPubMedGoogle Scholar
  42. Tomb, J.F., White, O., Kerlavage, A.R., et al. 1997. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388:539–547.CrossRefPubMedGoogle Scholar
  43. Tsutsumi, R., Takahashi, A., Azuma, T., et al. 2006. FAK is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. Mol Cell Biol 26:261–276.CrossRefPubMedGoogle Scholar
  44. van Doorn, L.J., Figueiredo, C., Megraud, F., et al. 1999. Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology 116:823–830.CrossRefPubMedGoogle Scholar
  45. Yamaoka, Y., El-Zimaity, H.M., Gutierrez, O., et al. 1999. Relationship between the cagA 3′ repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. Gastroenterology 117:342–349.CrossRefPubMedGoogle Scholar
  46. Yamaoka, Y., Kodama, T., Kashima, K., et al. 1998. Variants of the 3′ region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases. J Clin Microbiol 36:2258–2263.PubMedGoogle Scholar
  47. Yamazaki, S., Yamakawa, A., Ito, Y., et al. 2003. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J Infect Dis 187:334–337.CrossRefPubMedGoogle Scholar

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© Springer Science + Business Media, LLC 2009

Authors and Affiliations

  • Takeshi Azuma
    • 1
  1. 1.Department of GastroenterologyKobe University School of MedicineKobeJapan

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